GB2050827A - Topical compositions comprising isorbide dinitrate - Google Patents

Description

1

SPECIFICATION

Preparing compositions comprising isosorbide dinitrate GB 2 050 827 A 1 Organic nitrates such as nitroglycerin and isosorbide dinitrate have been successfully used for the treatment of coronary heart diseases. Recently, it has been reported that nitroglycerin ointments have a longer duration of efficiency than when the compound is administered orally. This longer duration of efficiency has been reported by Meister etal, British Heart Journal 38 (1976) 1031ff; Parker etal, The American Journal of Cardiology 38 (1976) 2:162ff; Reichek, Circulation 50 (1974) 348ff; Taylor, The American Journal of Cardiology 38 (1976) 469ff; Abrams, Clinical Research 24 (1976) 79A; Hanak etal, Therapiewoch 28 (1978) 40:10 7447-61 and Armstrong, The American Journal of Cardiology 38 (1976) 474ff.

U.S. Patent Specification No. 4,112,115 suggests the application of isosorbide dinitrate with a carrier, the isosorbide dinitrate being in true solution in one or several phases of the carrier. However, with such true solutions, it is difficult to achieve long durations of activity.

When administered orally, the organic nitrates mentioned enter the liver immediately where a large 15 proportion thereof is metabolised to relatively or wholly inactive metabolites. When administered topically, the organic nitrates do not first enter the liver and only subsequently the systemic circulation.

It would be desirable to provide a transclermal medication system comprising isosorbide dinitrate which could be administered topically on human skin, which could be dosaged simply and accurately, which could be easily rubbed in without leaving a repellent fatty orfat-like film on the skin, which was characterised by a 20 high resorption rate of the active ingredient without using known but undesirable carriers such as climethyl sulphoxide or dimethylacetamide, and which could provide a long duration of activity by providing a depot of undissolved active ingredient.

A pharmaceutical composition according to the present invention comprises from 2 to 20% by weight of isosorbide dinitrate; a solvent for the isosorbide dinitrate; anointment consistency agent; from 0 to 15% by 25 weight of an emulsifying agent; and water; in which the weight ratio of water: ointment consistency agent plus any emulsifying agent: solvent is 30 to 80:3 to 35:3 to 35.

The solvent for the isosorbide dinitrate preferably dissolves at least 5, and more preferably at least 10, % by weight isosorbide dinitrate (based on the solvent) and which is miscible, preferably wholly miscible, with water and has an ointment-like consistency (solidifying point below 400C) or is liquid (boiling point above 1000C). The solvent is preferably less volatile than water. Examples of suitable solvents are alkoxylated esters of a C8.18 fatty acid with glycerin. The degree of alkoxylation, and preferably ethoxylation, may be, for example, from 3 to 10, e.g. about 7, mole alkylene oxide.

The ointment consistency agent may be, for example, a mono- or poly-ester of polyfunctional aliphatic alcohol and an optionally hydroxylated fatty acid having at least 8 carbon atoms; a mono- or poly-ester of a 35 polyfunctional aliphatic carboxylic acid with a fatty alcohol having at least 8 carbon atoms; and/or a fatty acid or alcohol having at least 10 carbon atoms. Examples of suitable consistency agents are glycerin monostearate, hardened caster oil, cetyl alcohol, stearyl alcohol and stearic acid.

The consistency agent will often have emulsifying properties. It will, however, often be desirable to include a distinct agent having emulsifying properties, e.g. an ester of a polyalkylene diol with a fatty acid or a polyalkylene diol which has been etherified with a fatty alcohol. An example fo such an emulsifying agent is the stearate of polyethylene glycol, the average molecular weight of the glycol being about 100. The amount of added emulsifying agent is preferably from 0.5 to 15, and more preferably from 1 to 10, % by weight of the total weight of the composition.

The composition of the invention contains water. After application to human skin, the temperature of which is about 30'C, the water content decreases and approaches equilibrium. It is possible to select the components of the composition in such a manner that the weight ratio of dissolved to undissolved isosorbide dinitrate is from 1:99 to 60:40 and more preferably from 5:95 to 60:40 when equilibrium has been, or has closely been, reached. A dissolved to undissolved isosorbide dinitrate weight ratio within the given ranges ensures that the concentration of dissolved isosorbide dinitrate is suff iciently high to achieve a satisfactory resorption rate and that the amount of undissolved isosorbide dinitrate is sufficiently large to achieve a long duration of activity. The possibility of achieving the desired weight ratio has been tested in vitro using a 0.5 mm thick fIm applied to an impermeable support at 300C under 70% humidity.

The isosorbide dinitrate may be in particulate form. Preferably at least 90% by weight of the isosorbide dinitrate particles are less than 100, and more preferably less than 60 tm long and less than 20, and more 55 preferably less than 10 lim wide. By using particles of the preferred size, fast supplementary dissolution of isosorbide dinitrate crystals can be achieved.

The composition of the invention may comprise, in addition to the ingredients specified above, conventional preservatives, anti-oxidants, pH regulators and/or fragrances.

The composition of this invention may be prepared by melting a mixture of isosorbide dinitrate, the 60 ointment consistency agent, the solvent and any added emulsifying agent, and chilling the melt in water. All or part of the desired total amount of each ingredient can be used in this process; if only part, then the remainder can be added after the chilling step. Conventional additives such as preservatives etc. can be added before production of the melt or to the melt before or after the chilling step. The given process ensures that the composition contains finely divided isosorbide dinitrate.

2 GB 2 050 827 A 2 Byway of example, the melt maybe formed at a temperature of 55 to 75, and preferably from 63 to 67,C and added to water with stirring, the water being at a temperature of from 0 to 25, preferably 1 to 5 and more preferably 1 to 2,'C. It is desirable that the stirring should be intensive.

Compositions of the invention comprise a large proportion of water. Accordingly, they can be dosaged 5 accurately using, for example, a dosimeter. Suitable metering apparatus is described in Germany Patent Specification No. 1625200. Further, the large amount of water allows compositions of the invention to be easily rubbed into human skin without leaving anyfattyfilm. Clothes are not soiled by contact with the compositions, so that the patient's attitude is not negatively influenced in this respect. Moreover, the composition can be applied uniformly.

It will be apparentfrom the described process for the preparation of compositions of the invention that part of the dissolved isosorbide dinitrate is precipitated when the melt is added to water. The resultant composition therefore contains undissolved isosorbide dinitrate. The initial resorption is due to the dissolved active ingredient, while the undissolved active ingredient acts as a depot and can provide a long duration of activity.

In the described process, the chilling of the melt in water results in the active ingredient being finely divided, giving rise to fast dissolution. Since the concentration of dissolved active ingredient in the composition is small, any recrystallisation and/or crystal growth is suppressed so that fast dissolubility is maintained after application of the composition and the establishment of an equilibrium, as described above.

It might have been expected that, on account of the high water content, the resorption rate would have 20 been low (the saturation concentration of isosorbide dinitrate in water is only about 0.7 g/1). However, in the absence of water, a composition comprising solely isosorbide dinitrate and an ointment base would be fatty, difficult to dose, and would give low resorption. While the resportion rate could be improved by adding a solvent, as in US Patent Specification No. 4,112,115, the composition of that specification does not exhibit a long duration of activity. It is therefore surprising that compositions of the invention can exhibit good emulsion stability, easy dosability and a high resorption rate, without the use of toxic entraining materials such as dimethyl sulphoxide or dimethylacetamide. Nevertheless, the following Examples which illustrate the invention show good results.

Comparative ExampleA Awater-containing hydrophilic ointment containing 10% by weight 14C_Iabelled isosorbide dinitrate was prepared according to Deutsches Arzneibuch, 8th edition, page 436. At least 90% of the isosorbide dinitrate particles were not more that 100 gm long. This ointment was applied to a sample of five rats and the average radioactivity in the plasma and the cumulative secretion into the urine were measured. The results are shown in Figures 1 and 3. Dosability and resorption rate were unsatisfactory.

c 4 Comparative Example B An ointmentwas prepared from 10 parts by weight of isosorbide dinitrate, 78 parts by weight of a C8-18 fatty acid ester of glycerin ethoxylated with about 7 mol ethylene oxide as solvent, 4 parts by weight of hardened castor oil as a consistency agent and 8 parts by weight of 2- octyldodecanol as an emulsifying 40 agent (weight ratio of consistency agent plus enulsifying agent: solvent= 3:21.5) This ointment was applied to rats and tested in the same manner as that of Comparative Example A. A higher plasma level and a higher resorption rate than in Comparative Example A were observed.

Example 1

An ointment of the same composition as in Comparative Example B was prepared but which additionally comprised 80 parts by weight of water (weight ratio of water: consistency agent plus emulsifying agenesolvent = 30:4.5:29.2). This ointment comprised 5.0% by weight isosorbide dinitrate and 4.5% by weight additional emulsifying agent.

It was observed that, on application of the ointment of this Example to the skin, most of the water therein evaporated and a water equilibrium was established.

- 1 i 3 Example 2

200.0 kg of a composition was prepared from the following ing redients, in 8 units:

GB 2 050 827 A 3 1 Isosorbide dinitrate 20 kg Glycerin monostearate 11 kg 5 Polyoxyethylene stearate (average mole- 9 kg cular weight of polyoxyethylene 100) 2. CB-18 fatty acid ester of a glycerin 20.0 kg ethoxylated with about 7 mol ethylene oxide 10 3. Sorbic acid 0.33 kg 4. Ascorbyl palmitate 0.11 kg 5. Citric acid 0.2 kg 6. Sodium ethylenediaminetetraacetic acid 0.028 kg 7. Creme perfume oil)/017681 ("Dragoco") 0.1 kg 15 8. Water 139.232 kg Components 3 and 4 were carefully mixed together and ground with about 0. 8 kg of component 2 which was added in small portions to avoid the formation of lumps.

A clear melt was formed by heating component 1 and the remaining 19.2 kg of component 2 to 70-75'C in a reactor equipped with a cover which could be screwed down, an observation window and a stirrer. The melt was steadily stirred and adjusted to a temperature of 63-67'C. The ground mixture of components 3, 4 and part of 2 was added and the melt stirred further until a clear solution was formed. Cooling of the melt below 60'C was avoided (otherwise isosorbide dinitrate would precipitate and the melt would have needed to be heated above 700C, thereby possibly affecting the stability of the ascorbyl palmitate).

Components 5 and 6 were dissolved in a second (Brogli) reactor equipped with a stirrer and a homogeniser, in water. The aqueous phase was cooled to 1-2'C and a vacuum of at least -0.8 kg. cm2 was applied. The melt was then sucked into the reactor over about 15 minutes with cooling while the temperature of the melt was maintained at 63-67C and the homogeniser was still on.

After sucking in the melt, stirring was continued for 1 hour under a vacuum of less than -0.8 kg cmz. 30 Component 7 was then sucked into the reactor through the homogeniser while the system was stirred for a further 5 minutes. The stirrer and homogeniser were then switched off and the vacuum was broken by slow ventilation.

Several glass bottles were each filled 90 g of the thus-prepared composition. The glass bottles were each equipped with cream pumps U 10 V, Deutsche Aerosol Ventile GmbH). The stroke of which was adjusted to 35 500 mg.

A "nominal" dosage of 100 mg isosorbide dinitrate (from the composition of Example 2) was applied to human skin; the average concentration of the active ingredient was 1-2 mg ml overthe first 90 minutes and reached 6.2 mg ml after 6 hours. The average concentration then dropped gradually to 2.9 mg. ml after 12 hours and to 1.2 mg ml after 24 hours. A measurable level of the active ingredient was still present after 32 40 hours.

By comparison, when a tablet containing 5 mg isasorbide dinitrate was administered sublingually, the highest level of the active ingredient in the plasma 0 5.9 mg mill was reached after 30 minutes; the level then dropped with a half-life period of about 50 minutes.

-45 These tests show that topical application of compositions of the invention provide relatively long periods 45 of activity. For further details, compare Mansel Jones et al, Therapiewoche 28 (1978) 6537-6540.

Eleven patients having a clinically and electrocardiographically confirmed coronary heart disease were treated with a composition of Example 2. The ST line decrease was measured under ergometric control at the beginning of the treatment and after 3,5 and 7 hours, reflecting the degree of heart disease and the efficiency of the drug. The reference value, atthe start of the treatment, was 2.7 mm. The respective values 50 after 3, 5 and 7 hours were 1.2, 1.0 and 0.9 mm and a drop inefficiency could not be observed even after 7 hours (see the publication by Professor Brunner, Bonolo Hospital, Jaffa, Israel).

Claims (17)

1. A process for preparing a pharmaceutical composition, which comprises mixing from 2 to 20% by weight of isosorbide dinitrate; a solvent for the isosorbide dinitrate; anointment consistency agent; from 0 to 15% by weight of an emulsifying agent; and water; in which the weight ratio of water:ointment consistency agent plus any emulsifying agenesolvent is 30 to 80:3 to 35:3 to 35.

2. A process according to claim 1 in which from 0.5 to 10% by weight of the emulsifier is used.

3. A process according to claim 1 or claim 2 in which the solvent dissolves at least 511. w w isosorbide dinitrate, is miscible with water and has a solidifying point below 402C or a boiling point above 1 00'C.

4. A process according to claim 3 in which the solvent dissolves at least 101. w w isosorbide di nitrate.

5. A process according to any preceding claim in which the solvent is an ester of a C8.18 fatty acid with a glycerin alkoxylated with 3 to 10 mol alkylene oxide.

4 GB 2 050 827 A 4

6. A process according to any preceding claim in which the consistency agent is a mono- or poly-ester of a polyfunctional aliphatic alcohol and a fatty acid or a hydroxy fatty acid having at least 8 carbon atoms; a mono- or poly-ester of a polyfunctional aliphatic carboxylic acid with a fatty alcohol having at least 8 carbon atoms; and/or a fatty acid or alcohol having at least 10 carbon atoms.

7. A process according to any preceding claim in which the consistency agent is glycerine monostearate, hardened castor oil, cetyl alcohol, stearyl alcohol or stearic acid, or a mixture thereof.

8. A process according to any preceding claim in which any emulsifying agent is an ester of a polyalkylene diol with a fatty acid or a polyalkalene diol which is etherified with a fatty alcohol.

9. A process according to claim 8 in which any emulsifying agent is the stearate of a polyethylene glycol having an average molecular weight of about 100.

10. A process according to any preceding claim in which a mixture of isosorbide dinitrate, consistency agent, solvent and any emulsifying agent is melted and the melt is chilled in water.

11. A process according to claim 10 in which the melt is formed at from 55 to 75T, and added to water having a temperature of from 0 to 250C with stirring.

12. A process according to claim 1 substantially as described in any of the Examples.

13. A composition prepared by a process according to any preceding claim.

14. A composition according to claim 13 which, after reaching water equilibrium at about 300C, has a weight ratio of dissolved to undissolved isosorbide dinitrate of 1 to 60:99 to 40.

15. A composition according to claim 14 in which the weight ratio of dissolved to undissolved isosorbide dinitrate is from 5 to 60:95 to 40.

16. A composition according to any of claims 13 to 15 in which at least 90% by weight of the isosorbide dinitrate is in particulate form, the particles being less than 100 Itm long and less than 20 gm wide.

17. A composition according to claim 16 in which the isosorbide dinitrate particles are less than 10 X 60 Rm.

k Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980.

Published by the Patent Office, 25 Southampton Buildings, London, WC2A 'I AY, from which copies may be obtained.

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